Diabetes has become the third ranked non-infectious disease after the cardiovascular and cerebrovascular diseases and tumors. WHO predicts that by year 2030, the population of diabetes patients worldwide will be more than 360 million, more than 90% of which are with type II diabetes. Type II diabetes refers to non-insulin-dependent diabetes mellitus or adult-onset diabetes, and is becoming more common. Type II diabetes is increasing at an alarming rate. Despite the advance in the treatment of diabetes, hypoglycemic episodes are often the limiting factor in achieving optimal blood sugar control. To address the limitation of current diabetes treatment, much progress has been made in the research of glucagon-like peptide-1 (Glucagon-like peptide-1, referred to as GLP-1). GLP-1 as gut hormone is secreted by intestinal L cells. It is a potent antihyperglycemic hormone inducing glucose-dependent stimulation of insulin secretion promote while suppressing glucagon secretion. GLP-1 appears to restore the glucose sensitivity of pancreatic β-cells, with the mechanism possibly involving the increased expression of GLUT2 and glucokinase. GLP-1 is also known to inhibit pancreatic β-cell apoptosis and stimulate the proliferation and differentiation of insulin-secreting β-cells. GLP-1 secretion plays an important role in the pathogenesis of type II diabetes. It has been reported that GLP-1 secretion from L-cells is reduced in patients with type II diabetes even though is still insulinotropic in T2DM have prompted several hypotheses about how this affects the estimated clinical effectiveness of these novel drugs. GLP-1 secretion by intestinal L cells in the circulation is dependent on the presence of nutrients in the lumen of the small intestine. The secretagogues (agents that cause or stimulate secretion) of this hormone include major nutrients like carbohydrate, protein and lipid. It is a potent antihyperglycemic hormone, inducing glucose-dependent stimulation of insulin secretion while suppressing glucagon secretion. Such glucose-dependent action is particularly attractive as novel diabetes treatment, because when the plasma glucose concentration is in the normal fasting range, GLP-1 no longer stimulates insulin to cause hypoglycemia.
The therapeutic potential for GLP-1 and its analogs is further increased if one considers its use in patients with type I diabetes. A number studies have demonstrated the effectiveness of native GLP-1 in the treatment of insulin dependent diabetes mellitus (IDDM). Similar to non-insulin dependent diabetes mellitus (NIDDM) patients, GLP-1 is effective in reducing fasting hyperglycemia through its glucagonostatic properties. Additional studies have indicated that GLP-1 also reduces postprandial glycemic excursion in IDDM, most likely through a delaying in gastric emptying. These observations suggest that GLP-1 may be useful as a treatment for IDDM as well as for NIDDM.
However, the biologic half-life of native GLP-1 molecules which are affected by the activity of dipeptidyl-peptidase IV (DPP IV) is quite short. For example, the biological half-life of GLP-1(7-37)OH is only 3 to 5 minutes. Sustained lowering of blood glucose concentration is only observed with continuous infusion, as demonstrated in studies in which GLP-1 was administered by intravenous infusion over a 24-hour period. Therefore extended-action GLP-1 based peptides that are resistant to DPP IV may have great therapeutic potential for treatment of diabetes mellitus.